Fosfomycin formulation for parenteral administration

ABSTRACT

The field of the present invention is that of fosfomycin formulations for parenteral administration, in particular for intravenous administration. Formulations of the prior art provide fosfomycin as a powder to be diluted directly prior to the administration. The aim of the invention is to provide a fosfomycin formulation for parenteral administration which is easier to produce and administer or which lowers the risk of puncture injuries for healthcare professionals and the health risks for the patients (for example due to contamination or incorrect dosages) by preventing additional processing steps. During the course of the invention, it was surprisingly shown that fosfomycin is much more stable in an aqueous solution than what is commonly assumed. The invention therefore provides a closed container which contains an aqueous solution for parenteral administration, wherein at least one pharmaceutically acceptable salt of fosfomycin, in particular fosfomycin disodium salt, and a pharmaceutically acceptable acid, in particular succinic acid, are dissolved in the solution. Preferred containers are breakable ampoules made of plastic or glass, puncturable vials, infusion bags, or syringes ready for injection.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is the National Stage of International Application No.PCT/EP2017/056252, filed on Mar. 16, 2017 claiming the priority of EP16160698.3, filed on Mar. 16, 2016, the content of each of which isincorporated by reference herein.

The field of the present invention is that of fosfomycin formulationsfor parenteral administration, particularly for intravenousadministration.

The antibiotic fosfomycin is a structurally unique substance within theantibiotics and was originally isolated from Streptomyces fradiae.Parenterally, fosfomycin is administered intravenously orintramuscularly, for example, and is commonly used for targeted therapyof infections in particular in the medical critical care, especially ifresistance or intolerance can be expected with regard to otherantibiotics. Clinical applications for the use of fosfomycin are amongothers: in the area of the central nervous system, meningitis,meningoencephalitis, cerebral abscess, and subdural emphysema; insurgery, postoperative infections, concomitant infections in tumors andprostatitis; in orthopedics and traumatology, postoperative boneinfections (infected osteosynthesis, endoprosthesis), osteomyelitis,purulent arthritis, abscesses, and phlegmons; in the area of therespiratory tract, bronchopneumonia, pulmonary abscess, and sinusitis;and sepsis.

Fosfomycin disodium salt is a common pharmaceutically acceptable salt offosfomycin. It is a white or almost white, very hygroscopic powder thatis highly soluble in water. Fosfomycin which is dissolved in watercannot be administered parenterally due to the high pH value of thesolution. In order to achieve a tissue-compatible or vein acceptable pH,succinic acid is therefore added to currently available preparations forparenteral administration.

Currently, succinic acid is added in the form of a powder by sterilemixing it with fosfomycin as a powder. This mixture is filled as apowder into puncturable vials and put on the market in this form. Inthis form of a dry substance for infusion preparation approved inindividual countries of the European Union are for example FosfomycinAstro (Astro-Pharma GmbH, Vienna, AT), Fosfomycin medicamentum(medicamentum pharma GmbH, Allerheiligen, AT) und Fosfomycin Sandoz®(Sandoz GmbH, Kundl, AT) in Austria, Fosfomycin Infectopharm®(Infectopharm Arzneimittel und Consilium GmbH, Heppenheim, DE) inGermany, and Fomicyt® (Infectopharm Arzneimittel und Consilium GmbH,Heppenheim, DE) in the United Kingdom.

Directly prior to the parenteral administration such dry substances haveto be dissolved in a suitable solvent by the medical personnel.

The current procedure causes various problems. The physical sterilemixing of dry substances is very complex as it is necessary, forexample, to ensure the uniformity of the mixture, i.e. no demixing orcaking of the powder must occur. This requires a complicated technologywhich is mastered only by a few manufacturers under the required GoodManufacturing Practice (GMP) conditions. This results in ongoing supplyshortages in the supply of fosfomycin for parenteral administration. Forexample, according to an information from the Federal Office for Safetyin Health Care, all formulations of fosfomycin approved for parenteraladministration have been unavailable in Austria since June 2015 and areexpected to remain unavailable until at least March 2016 (status as ofFebruary 2016).

In addition, the processing step required by the health careprofessionals to obtain a solution for infusion poses a health risk forboth the personnel and the patient, especially if the susceptibility tohuman error is increased by a high workload. Firstly, the processingstep itself poses an additional risk of puncture wounds to thepersonnel. Secondly, the risk of a dangerous contamination or wrongdosage to the patient is increased by the additional processing step.And thirdly, when the dry substance contains, as usual, fosfomycindisodium salt (regular doses of about 4 to 8 grams include about 60 to120 mmol sodium ions), and the dry substance is dissolved, due to anerror and contrary to the package information leaflet, in physiologicalsaline and is administered in this way, the patient may suffer asometimes fatal hypernatremia due to the excess of sodium ions resultingfrom this.

Some of these problems are also recognized by DE 20 2008 012 514 U1.This document proposes as an approach a packaging unit for providing aparenterally administrable, pharmacologically acceptable pharmaceuticalformulation, comprised of the antibiotic fosfomycin and succinic acid oranother biocompatible acid, characterized in that the unit consists ofone container which is sterile filled with fosfomycin in powder form,and another container which is sterile filled with the acid, dissolvedin an pharmacologically acceptable solvent.

An object of the present invention is hence to provide a fosfomycinformulation for parenteral administration aimed at overcoming thedisadvantages of the prior art such as, inter alia, delivery bottlenecksdue to elaborate manufacturing and hazardous further processing stepsjust prior to administration, which, for example, are still needed inthe approach of DE 20 2008 012 514 U1. This means, it is an object ofthe present invention to provide a fosfomycin formulation für parenteraladministration which is easier to produce and to administer.

Surprisingly, it was demonstrated in the course of the present inventionthat fosfomycin is much more stable in an aqueous solution than wascommonly assumed. In the course of the present invention, the stabilityof fosfomycin in an aqueous solution in the presence of an acid wastested at different temperatures and time periods. Even after repeatedautoclaving at 125° C. and months of storage fosfomycin was effectiveagainst the tested bacteria such as Staphylococcus and Escherichia (seeexample 2 and FIGS. 1A-1D).

Therefore, the present invention provides a closed container whichcontains an aqueous solution for parenteral administration, wherein apharmaceutically acceptable salt of fosfomycin and a pharmaceuticallyacceptable acid are dissolved in said solution. In the solution, furtheractive ingredients and/or excipients may be included. It is convenientif the container is hermetic (or “hermetically sealed”), which, in otherwords, means that no gas exchange between the solution and theenvironment of the container is possible.

To reach to the present invention, the inventors had to overcome adeeply rooted prejudice in the prior art:

All fosfomycin formulations for parenteral administration of the priorart have in common their creators' assumption that fosfomycin is toounstable in solution and must thus be used as a powder in theformulation and must be dissolved just prior to administration. Thisprejudice is so deeply rooted in the prior art that, for example, thedry powder mixing of fosfomycin and succinic acid under GMP conditionsis performed under enormous effort, and that supply constraints, as setforth above, are accepted.

Thus, the Public Assessment Report (PL 15011/0014 of 1 Sep. 2014) ofMedicines & Healthcare Products Regulatory Agency (MHRA) recommends forFomicyt® to only use freshly prepared solution. The chemical stabilityof the ready-to-use, sterile-prepared solution is indicated to be 12hours at 2-8° C. when protected from light.

The leaflets of Fosfomycin Astro, Fosfomycin Sandoz®, Fosfomycinmedicamentum and Fosfomycin Infectopharm® all recommend to use onlyfreshly prepared solution. The chemical stability of the ready-to-use,sterile-prepared fosfomycin solution is indicated to be 24 hours at 25°C. when protected from light.

Quentin et al. (Quentin, Claudine, et al. “Stability of fosfomycin andquinolones in peritoneal dialysis solution.” Journal of AntimicrobialChemotherapy 25.5 (1990): 878-880) comes to the conclusion that certainfosfomycin solutions are stable for 24 hours at room temperature.

Bailie et al. (Bailie, George R., and Michael P. Kane. “Stability ofdrug additives to peritoneal dialysate.” Peritoneal dialysisinternational 15.8 (1995): 328-335.) also indicate the same results.

The following documents also do not anticipate the present invention,because they do not contain any concrete disclosure with respect to thepresent invention, nor do they lead up to it, because they provide theskilled person with no concrete clues with respect to the presentinvention.

WO 2014/040947 A1 refers to a an aerosol supply device having an openingelement. In this document, fosfomycin is mentioned as one among hundredsof most varied active substances which can optionally be administered byusing the aerosol supply device. For example, the particular combinationof the closed container, water, a pharmaceutically acceptable salt offosfomycin and a pharmaceutically acceptable acid is not disclosedtherein.

The same applies to EP 2062608 A2, which discloses a disposable glassvial for a device for generating aerosols.

WO 2008/071197 A1 refers to methods for the treatment of cystic fibrosisor bacterial pneumonia by the pulmonary administration of fosfomycin,but the specific combination of the closed container, water, apharmaceutically acceptable salt of fosfomycin and a pharmaceuticallyacceptable acid is not disclosed therein.

WO 2005/110022 A2 relates to a combination of fosfomycin andaminglycoside for the treatment of bacterial respiratory infections. Thespecific combination of a closed container, water, a pharmaceuticallyacceptable salt of fosfomycin and a pharmaceutically acceptable acid isnot disclosed therein. US 2015/0057242 A1 relates to a combination offosfomycin and aminoglycoside for the treatment of ventilator associatedpneumonia and ventilator associated bronchitis, which is administered byinhalation using a nebulizer and is provided for example in ampoules.However, the document neither discloses the storage conditions for suchampoules (e.g. with regard to storage temperature and duration) nor anytest results with regard to the storage stability of fosfomycin.

WO 2012/030513 A2 discloses methods for the treatment of bacterialinfections by pulmonary administration of fusidic acid, optionally incombination with tobramycin, amikacin, fosfomycin or levofloxacin. Forfosfomycin, only oral administration and pulmonary administration isproposed (see section “Fosfomycin Dosage Forms”, paragraphs [0092] and[0093] of said document), in contrast to others of said activeingredients (see section “Amikacin Dosage Forms” directly before, andsection “Levofloxacin Dosage Forms”, directly thereafter). For example,the particular combination of the closed container, water, apharmaceutically acceptable salt of fosfomycin and a pharmaceuticallyacceptable acid is not disclosed therein.

WO 2004/063036 A1 relates to a security container for biologicallyactive substances and processes for their preparation. In said document,fosfomycin is mentioned as one among thousands of most varied activesubstances which may be provided in the security container if necessary.For example, the particular combination of the closed container, water,a pharmaceutically acceptable salt of fosfomycin and a pharmaceuticallyacceptable acid is not disclosed therein.

Finally, WO 2010/048059 A1 relates to combinations of fosfomycin andtobramycin for the treatment or prevention of ophthalmic, otological anddermatological infections. However, the particular combination of theclosed container, water, a pharmaceutically acceptable salt offosfomycin and a pharmaceutically acceptable acid in the same solutionis not disclosed therein. Remarkably, it is specifically disclosed inrelation to the packaging that fosfomycin is separately stored in ablister pack (i.e. dry) for long-term stabilization and is added to thetobramycin solution just prior to use (page 24, 1st paragraph of thatdocument).

In a preferred embodiment of the present invention, the aqueous solutioncontained in the closed container of the invention is for infusion orinjection into the body of a mammal, especially a human being.Preferably, said mammal or human being is a patient who is sufferingfrom a bacterial infection.

In a further preferred embodiment of the present invention, the aqueoussolution is provided for an administration selected from intravenousadministration, intramuscular administration, intraosseousadministration, intravitreal administration, intraperitonealadministration, and intrathecal administration. Of these, particularlypreferred is intravenous administration.

In a most preferred embodiment, the aqueous solution is ready to use forparenteral administration. This means in particular that no dilution,mixing (especially with other substances), dissolution, orreconstitution prior to administration of the solution is requiredanymore. However, if the solution is not contained in a prefilledsyringe or an infusion bag, for example, then it has to be transferredinto another container suitable for administration, such as a syringe.Particularly preferably, the aqueous solution is ready to use forintravenous administration or ready to use for administration byinhalation.

Advantageously, the closed container of the present invention is sealed,inter alia, for reasons of tamper safety and also to prevent theaccidental reuse of an already opened and thereby potentiallycontaminated container. The term “sealed” in the context of the presentinvention means that an opening of the container which has occurredafter sealing is detectable and preferably visible even to the nakedeye, whereby said detectability and visibility cannot be reversedwithout at least some effort or without considerable effort. A person ofskill in the art is well-acquainted with the means for sealing in thepharmaceutical field; this includes, for example, release liners, tearlabels, void sealing, sealing with zipper perforations, and perforationsof screw caps (“freshness seal”). Preferably, the sealing of the closedcontainer of the invention or the container according to the inventioncomplies with the norm DIN EN 16679: 2015-03.

For similar reasons as mentioned in the previous paragraph, inter alia,the container is, in a further preferred embodiment of the presentinvention, closed in a manner, in which an opening of the container issubstantially permanent (i.e. to be reversed only with considerableeffort). A typical example is breakable ampoules such as made of plasticor glass. A breakable ampoule is known for example from EP 0 243 580 A1or EP 0 350 772 A1.

In a further preferred embodiment, the closed container of the inventionis selected from:

an ampoule, in particular made of plastic or glass, preferably abreakable ampoule, in particular made of plastic or glass (any containerhaving a closure, which must be broken up, is encompassed within thecontext of the present invention by the term “breakable ampoule”);

a puncturable vial (also called “vial”; see e.g. WO 2006/072440 A1),preferably sealed with a protective cap;

an infusion bag or an infusion bottle (e.g. with a Luer-Lock or rubberplug, optionally with graduation), and

a syringe, especially a syringe ready for injection. The container maybe made of a transparent or non-transparent material. Preferably, thecontainer constitutes a light protection for the solution (in particularin the UV/VIS range). The container may be substantially opaque oropaque (in particular in the UV/VIS range). Preferably, the container isa disposable container or for single use.

It is convenient if the container, especially if it is a vial or anintravenous bag, has an intact septum, for example of rubber, or all thesepta of the container are intact.

In a further preferred embodiment of the present invention, thepharmaceutically acceptable salt of fosfomycin is selected fromfosfomycin disodium salt, fosfomycin monosodium salt, a potassium saltof fosfomycin, a fosfomycin lithium salt, fosfomycin magnesium salt, andfosfomycin calcium salt. Particularly preferred are the sodium salts, inparticular fosfomycin disodium salt.

In a further preferred embodiment, the pharmaceutically acceptable acidis a weak acid or an organic acid, preferably a weak organic acid. Weakacids are particularly preferred for their buffering effect. Inparticular, the preferable organic acid has a pKa value at 25° C. of 2to 9, preferably from 2.5 to 8, more preferably from 3 to 7, even morepreferably from 3.5 to 6.5, in particular from 4 to 6, and preferablyall pKa values of the acid (if the acid has multiple pKa values) are,independently of each other, within one of these intervals. Preferably,the pharmaceutically acceptable acid is tolerated by the veins.

In a further particularly preferred embodiment of the present invention,the pharmaceutically acceptable acid is selected from succinic acid,tartaric acid, lactic acid, malic acid, citric acid, carbonic acid,amino acids, acetic acid, and phosphoric acid. Succinic acid is mostpreferred, especially for intravenous administration.

It is convenient if in the aqueous solution contained in the closedcontainer of the invention essentially the following components aredissolved: a pharmaceutically acceptable salt of fosfomycin and apharmaceutically acceptable acid, optionally with glucose or fructose(for example in a concentration of 1% to 5% w/v).

In a further preferred embodiment, the aqueous solution contains onlyfosfomycin as an antibiotic. Preferably the aqueous solution containsjust fosfomycin as the only active ingredient (with the pharmaceuticallyacceptable acid as an adjuvant), optionally with further excipients, inparticular glucose or fructose (e.g. in a concentration of 1% to 5%w/v).

In a highly preferred embodiment of the present invention, essentiallyonly fosfomycin disodium salt and succinic acid are dissolved in theaqueous solution, optionally with glucose or fructose (e.g. in aconcentration of 1% to 5% w/v).

In a further preferred embodiment, the aqueous solution has a pH(preferably at 25° C.) of less than 10.0, preferably of less than 9.0,more preferably of less than 8.5, even more preferably of less than 8.0,in particular of less than 7.75, or even of at most 7.5.

In a further preferred embodiment the aqueous solution has a pH(preferably at 25° C.) of 3 to 9, preferably from 4 to 8.5, morepreferably from 5 to 8.5, in particular from 6 to less than 8.0.

In a further particularly preferred embodiment, the aqueous solution hasa pH (preferably at 25° C.) of 6.4 to 8.4, preferably of greater than6.5 and less than 8.0, more preferably of 6.9 to 7.9, more preferably of7.0 to 7.8, even more preferred of 7.1 to 7.7, in particular of 7.2 to7.6 or even of 7.3 to 7.5. In particular this embodiment is suitable forinfusion or injection or intravenous administration, with pH values thatare as close to the normal pH of human blood (7.35-7.45) as possiblebeing particularly suitable.

In a further preferred embodiment, the aqueous solution (especially whenready to use for intravenous administration) has an osmolarity of atmost 800 mosmol/L, preferably at most 600 mosmol/L, more preferably atmost 500 mosmol/L, even more preferably at most 450 mosmol/L, especiallyat most 400 mosmol/L, or even at most 350 mosmol/L; preferably at acertain minimum osmolarity of, for example, at least 50 mosmol/L, atleast 100 mosmol/L, or at least 200 mosmol/L. Most preferably, thesolution is isotonic or hypotonic (in respect to human blood plasma),preferably at a certain minimum osmolarity of, for example, at least 50mosmol/L, at least 100 mosmol/L, or at least 200 mosmol/L.

Advantageously, the aqueous solution in the closed container of thepresent invention contains a total dose of fosfomycin equivalent to 0.25to 15 grams of fosfomycin, preferably 0.5 to 10 grams of fosfomycin,more preferably from 0.75 to 8 grams of fosfomycin, particularly from 1to 4 grams of fosfomycin. In particular, the solution is provided as asingle dose. Preferably, the volume of the solution (in particular whenit is present ready for use) is between 1 ml and 100 ml/g of fosfomycin,preferably between 5 ml and 50 ml/g of fosfomycin, more preferablybetween 10 ml and 40 ml/g of fosfomycin, even more preferably between22.5 ml and 27.5 ml/g of fosfomycin, in particular at substantially 25ml/g of fosfomycin.

In a further preferred embodiment, the pharmaceutically acceptable acidis succinic acid and the mass ratio of succinic acid to fosfomycin inthe solution is between 30:1 and 50:1, in particular essentially 40:1.

It is convenient if the closed container of the invention has beensterile filled with the solution. In particular, the closed container isin accordance with the “EU Guidelines for Good Manufacturing Practicefor Medicinal Products for Human and Veterinary Use”, applicable on 15Feb. 2016, in particular to Annex 1, in the version of “25 Nov. 2008(rev.)”.

In a further preferred embodiment, the container has been filled withthe aqueous solution and closed according to Annex 1 of the “EUGuidelines for Good Manufacturing Practice for Medicinal Products forHuman and Veterinary Use”, as amended on “25 Nov. 2008 (rev.)”.

Due to the surprising finding that fosfomycin is so stable in solution,it is now possible to provide it in the industrial production insolution with an antifungal agent (in particular, ready to use forparenteral or inhalation administration). Such a combination product isparticularly suitable for patients with cystic fibrosis(mucoviscidosis), the respiratory tract and lungs of whom are vulnerableto infections by bacteria and fungi. It is therefore preferred if thesolution in the closed container further comprises an antifungal agentwhich is preferably selected from the group consisting of terbinafine,naftifine, butenafine, and pharmaceutically acceptable salts thereof.The solution may have a total dose of 10 mg to 5000 mg, preferably from20 mg to 2000 mg, more preferably from 30 mg to 1000 mg, even morepreferably from 40 mg to 500 mg, in particular from 50 mg to 250 mg ofsaid antifungal agent.

In a particularly preferred embodiment, the antifungal agent isterbinafine or a pharmaceutically acceptable salt thereof. It ispreferred that the solution contains a total dose of terbinafineequivalent to 10 mg to 2000 mg of terbinafine, preferably from 20 mg to1000 mg of terbinafine, more preferably from 30 mg to 500 mg ofterbinafine, even more preferably from 40 mg to 250 mg of terbinafine,in particular from 50 mg to 200 mg, or even from 50 mg to 100 mg ofterbinafine. The mass ratio of terbinafine to fosfomycin in the solutionis usually between 1:1 and 1:200, preferably between 1:2 and 1:100, morepreferably between 1:3 and 1:75, even more preferably between 1:4 and1:50, in particular between 1:5 to 1:25.

In a further aspect, the present invention relates to a packagecomprising at least one closed container of the invention. The packagemay be made, inter alia, from cardboard, especially from printedcardboard. The package preferably comprises a leaflet. Preferably, thepackage constitutes a light protection for the solution or the container(especially in the UV/VIS range). The package may be substantiallyopaque or opaque (in particular in the UV/VIS range). Preferably, thepackage additionally preserves the sterility of the closed container(and thus its outer surface), for example when the package or a partthereof is constructed as a plastic film.

Advantageously, the package of the invention is sealed, among otherthings for reasons of security against manipulation or also to preventaccidental reuse. The term “sealed” means in this context that anopening of the package, which took place after the sealing, isdetectable, and preferably visible even to the naked eye, wherein saiddetectability and visibility cannot be reversed at least not withouteffort or without substantial effort. To the skilled person, the meansfor sealing of packages in the pharmaceutical field are known, and theseinclude, for example, release liners, tear labels and VOID seals.Preferably, the sealing of the package of the invention or the packagingof the invention complies with the standard of DIN EN 16679:2015-03.

In a particularly preferred embodiment, the package further comprises anantifungal agent, in particular terbinafine. Typically, the antifungalagent is contained in the solution of fosfomycin.

In a further aspect, the present invention relates to the storing of theclosed container of the invention or the package of the invention at atemperature of between 0° C. and 60° C., in particular at a temperatureof 15° C. to 35° C. or at room temperature, for at least one week,preferably for at least one month, more preferably for at least threemonths, even more preferably for at least six months, especially for atleast one year or even for at least two years. Preferably, the storingtakes place under light protection (in particular in the UV/VIS range).

In a further aspect, the present invention relates to a processcomprising sterile filling the container with the solution and closingthe container. Preferred for a further step is sealing the closedcontainer, in particular according to the standard of DIN EN16679:2015-03.

Preferably, the aqueous solution is not produced from a sterile mixedpowder mixture of the pharmaceutically acceptable salt of fosfomycin anda pharmaceutically acceptable acid in accordance with the “EU Guidelinesfor Good Manufacturing Practice for Medicinal Products for Human andVeterinary Use”, applicable on 15 Feb. 2016, especially in accordancewith Annex 1 in the version of “25 Nov. 2008 (rev.)”.

In a further aspect, the present invention relates to a process for theproduction of the package of the invention, comprising carrying out themethod of the invention for the preparation of the closed container ofthe invention and the packing of the closed container into the package.Preferred for a further step is the sealing of the package, inparticular according to the standard of DIN EN 16679:2015-03.

In a further aspect, the present invention relates to fosfomycin for usein the prevention or treatment of an infection, particularly aninfection of the lower respiratory tract or the lung, in a patientsuffering from cystic fibrosis. Such patients are particularlysusceptible to respiratory or lung infections by bacteria or fungi whichmay occur repeatedly and may frequently become chronic. An overview ofthese issues is provided, for example, by Lyczak et al. (“Lunginfections associated with cystic fibrosis.” Clinical MicrobiologyReviews 15.2 (2002): 194-222.) or Gibson et al. (“Pathophysiology andmanagement of pulmonary infections in cystic fibrosis.” American Journalof Respiratory and Critical Care Medicine 168.8 (2003): 918-951. Becauseof the increased risk in terms of resistance, it is especially useful toalso have available comparatively rather uncommon antibiotics such asfosfomycin (or in systemic use comparatively rather uncommon antifungalagents such as terbinafine), which are already in solution for easy use(or even ready to use for parenteral or inhalation administration), asis achieved by the present invention. In addition, the use of lowerdoses or a more targeted application is enabled thereby, which in turnreduces the risk of resistances.

In this aspect, fosfomycin or a pharmaceutically acceptable salt thereofis usually administered in a solution parenterally, intravenously or byinhalation to the patient. Optionally, the solution also comprises anantifungal agent.

In a particularly preferred embodiment, fosfomycin or a pharmaceuticallyacceptable salt thereof is administered together with terbinafine or apharmaceutically acceptable salt thereof to the patient. Typically, atleast one of the administrations is parenterally or by inhalation. It isconvenient if fosfomycin or a pharmaceutically acceptable salt thereof,and terbinafine, or a pharmaceutically acceptable salt thereof isprovided in the same aqueous solution for a (preferably parenteral, inparticular inhalative) administration.

Further Definitions

Herein, “parenteral” must be interpreted in its broadest sense(bypassing of the intestine), i.e. all modes of administration otherthan the oral or rectal are encompassed by this term.

The aqueous solution is preferably liquid within the meaning of thepresent invention. In particular, it is not substantially different fromwater with respect to its viscosity at the same temperature. Preferably,the viscosity of the solution at 20° C. and normal pressure is between0.5 cP and 25 cP, preferably at about 1-2 cP, in particular at about 1cP. Preferably, the aqueous solution is not a suspension, emulsion,cream or gel.

Preferably, the water in the aqueous solution is water for injection, inparticular in accordance with Ph. Eur. (8th edition).

The present invention particularly relates to the following preferredembodiments:

EMBODIMENT 1

A closed container, comprising an aqueous solution for parenteraladministration, wherein at least a pharmaceutically acceptable salt offosfomycin and a pharmaceutically acceptable acid are dissolved in thesolution.

EMBODIMENT 2

A closed container according to embodiment 1, wherein said solution isready to use for parenteral administration.

EMBODIMENT 3

A closed container according to embodiment 2, wherein the solution isready to use for intravenous administration or ready to use forparenteral administration.

EMBODIMENT 4

A closed container according to any one of embodiments 1 to 3, whereinthe closed container is sealed.

EMBODIMENT 5

A closed container according to any one of embodiments 1 to 4, whereinthe container is closed in a manner that an opening of the container issubstantially irreversible.

EMBODIMENT 6

A closed container according to any one of embodiments 1 to 5, whereinthe container is selected from:

-   -   an ampoule in particular made of plastic or glass, preferably a        breakable ampoule in particular made of plastic or glass,    -   a puncturable vial, preferably sealed with a cap,    -   an infusion bag, and    -   a syringe, especially a syringe ready for injection.

EMBODIMENT 7

A closed container according to any one of embodiments 1 to 6, whereinthe container, which preferably is a puncturable vial or an infusionbag, has an intact septum for example made of rubber.

EMBODIMENT 8

A closed container according to any one of embodiments 1 to 7, whereinthe container serves as a light protection for the solution, and inparticular is substantially opaque.

EMBODIMENT 9

A closed container according to any one of embodiments 1 to 8, whereinthe pharmaceutically acceptable salt of fosfomycin is selected fromfosfomycin disodium salt, fosfomycin monosodium salt, a fosfomycinpotassium salt, a fosfomycin lithium salt, fosfomycin magnesium salt,and fosfomycin calcium salt.

EMBODIMENT 10

A closed container according to any one of embodiments 1 to 9, whereinthe pharmaceutically acceptable acid has a pKa value at 25° C. of 2 to9, wherein the acid is preferably selected from succinic acid, tartaricacid, lactic acid, malic acid, citric acid, carbonic acid, amino acids,acetic acid, and phosphoric acid.

EMBODIMENT 11

A closed container according to any one of embodiments 1 to 10, whereinthe only dissolved components in the solution are, in essence, apharmaceutically acceptable salt of fosfomycin and a pharmaceuticallyacceptable acid, optionally with glucose or fructose.

EMBODIMENT 12

A closed container according to embodiment 11, wherein only fosfomycindisodium salt and succinic acid are dissolved in the solution, inessence, optionally with glucose or fructose.

EMBODIMENT 13

A closed container according to any one of embodiments 1 to 12, whereinthe solution (preferably at 25° C.) has a pH value of 6.4 to 8.4,preferably of greater than 6.5 and less than 8.0, more preferably from6.9 to 7.9, more preferably from 7.0 to 7.8, even more preferably from7.1 to 7.7, in particular from 7.2 to 7.6 or even from 7.3 to 7.5; orwherein the solution (preferably at 25° C.) has a pH of less than 10.0,preferably of less than 9.0, more preferably of less than 8.5, even morepreferably of less than 8.0, in particular of less than 7.75 oder evenof at most 7.5; or wherein the solution (preferably at 25° C.) has a pHof 3 to 9, preferably of 4 to 8.5, more preferably from 5 to 8.5, inparticular from 6 to less than 8.0.

EMBODIMENT 14

A closed container according to any one of embodiments 1 to 13, whereinthe solution contains a total dose of fosfomycin equivalent to 0.25 to15 grams of fosfomycin, preferably from 0.5 to 10 grams of fosfomycin,more preferably from 0.75 to 8 grams of fosfomycin, in particular from 1to 4 grams of fosfomycin.

EMBODIMENT 15

A closed container according to any one of embodiments 1 to 14, whereinsaid pharmaceutically acceptable acid is succinic acid and the massratio of succinic acid to fosfomycin in the solution is between 30:1 and50:1, in particular at substantially 40:1.

EMBODIMENT 16

A closed container according to any one of embodiments 1 to 15, whereinthe container has been sterile filled with the solution.

EMBODIMENT 17

A closed container according to any one of embodiments 1 to 16, whereinthe closed container in accordance with the “EU Guidelines for GoodManufacturing Practice for Medicinal Products for Human and VeterinaryUse”, applicable on 15 Feb. 2016, in particular to Annex 1 in theversion of “25 Nov. 2008 (rev.)”.

EMBODIMENT 18

A closed container according to any one of embodiments 1 to 17, whereinthe container has been filled with the solution and closed according toAnnex 1 of the “EU Guidelines for Good Manufacturing Practice forMedicinal Products for Human and Veterinary Use” in the version of “25Nov. 2008 (rev.)”.

EMBODIMENT 19

A closed container according to any one of embodiments 1 to 10 and 13 to18, wherein the solution further comprises an antifungal agent dissolvedin it.

EMBODIMENT 20

A closed container according to embodiment 19, wherein the antifungalagent is selected from the group consisting of terbinafine, naftifine,butenafine, and pharmaceutically acceptable salts thereof.

EMBODIMENT 21

A closed container according to embodiment 20, wherein the antifungalagent is terbinafine or a pharmaceutically acceptable salt thereof.

EMBODIMENT 22

A closed container according to any one of embodiments 19 to 21, whereinthe solution contains a total dose of 10 mg to 5000 mg, preferably of 20mg to 2000 mg, more preferably of 30 mg to 1000 mg, even more preferablyof 40 mg to 500 mg, in particular of 50 mg to 250 mg of the antifungalagent.

EMBODIMENT 23

A closed container according to embodiment 21, wherein the solutioncontains a total dose of terbinafine equivalent to 10 mg to 2000 mg ofterbinafine, preferably to 20 mg to 1000 mg of terbinafine, morepreferably to 30 mg to 500 mg of terbinafine, even more preferably of 40mg to 250 mg of terbinafine, in particular of 50 mg to 200 mg or even of50 mg to 100 mg of terbinafine.

EMBODIMENT 24

A closed container according to embodiment 21, wherein the mass ratio ofterbinafine to fosfomycin in the solution is between 1:1 and 1:200,preferably between 1:2 and 1:100, more preferably between 1:3 and 1:75,even more preferably between 1:4 and 1:50, in particular between 1:5 and1:25.

EMBODIMENT 25

A package comprising at least one closed container according to any oneof embodiments 1 to 18 and preferably a leaflet.

EMBODIMENT 26

A package according to embodiment 25, further comprising an antifungalagent, in particular terbinafine, preferably wherein the antifungalagent is present as defined in one of the embodiments 19 to 24.

EMBODIMENT 27

A package according to embodiment 25 or 26, wherein the package servesas a light protection for the solution or the closed container, and isin particular substantially opaque.

EMBODIMENT 28

A method comprising the storing of the closed container of one of theembodiments 1 bis 24 or the package of one of the embodiments 25 to 27at a temperature between 0° C. and 60° C., in particular at atemperature of 15° C. to 35° C. or at room temperature, for at least oneweek, preferably for at least one month, more preferably for at leastthree months, even more preferably for at least six months, inparticular for at least one year, or even for at least two years.

EMBODIMENT 29

A method for the production of the closed container of any one ofembodiments 1 to 24, comprising sterile filling the container with thesolution and closing the container.

EMBODIMENT 30

The method of producing according to embodiment 29, further comprisingsealing the closed container.

EMBODIMENT 31

The method of production according to any one of embodiments 29 to 30,wherein the solution is not produced of a sterile mixed powder mixturein accordance with “EU Guidelines for Good Manufacturing Practice forMedicinal Products for Human and Veterinary Use”, applicable on 15 Feb.2016, and in particular in accordance with Annex 1 in the version of “25Nov. 2008 (rev.)”, of the pharmaceutically acceptable fosfomycin saltand the pharmaceutically acceptable acid

EMBODIMENT 32

A method for the production of the package according to any one ofembodiments 25 to 27, comprising performing the method according to anyone of embodiments 29 to 31, whereby said closed container is obtained,and packing the closed container into the package.

EMBODIMENT 33

Fosfomycin for use in the prevention or treatment of an infection,particularly an infection of the lower respiratory tract, in a patientsuffering from cystic fibrosis, wherein the fosfomycin or apharmaceutically acceptable salt thereof is administered parenterally,in particular intravenously or by inhalation, in a solution, as definedin any one of embodiments 1 to 18.

EMBODIMENT 34

Fosfomycin for use in the prevention or treatment of an infection,particularly an infection of the lower respiratory tract, in a patientsuffering from cystic fibrosis, wherein the fosfomycin or apharmaceutically acceptable salt thereof together with an antifungalagent is administered parenterally, in particular intravenously or byinhalation, in a solution, as defined in any one of embodiments 19 to24.

EMBODIMENT 35

Fosfomycin for use in the prevention or treatment of an infection,particularly an infection of the lower respiratory tract, in a patientsuffering from cystic fibrosis, wherein the fosfomycin or apharmaceutically acceptable salt thereof together with terbinafine or apharmaceutically acceptable salt thereof is administered parenterally,in particular intravenously or by inhalation, to the patient.

EMBODIMENT 36

Fosfomycin for use according to embodiment 35, wherein fosfomycin or apharmaceutically acceptable salt thereof and terbinafine or apharmaceutically acceptable salt thereof is present in the same aqueoussolution for administration.

The invention is further illustrated by the following examples andfigures to which it is of course not limited.

FIGS. 1A-1D: Minimal Inhibitory Concentration (MIC) of a fosfomycin acidsolution as a function of storage time and temperature with respect toStaphylococcus aureus ATTC 49775 (FIG. 1A), Staphylococcus aureus ATTC33592 (FIG. 1B), Staphylococcus hominis AG 1115 (FIG. 1C) andEscherichia coli AG 1215 (FIG. 1D). The lower the MIC of an antibiotic,the stronger the antimicrobial effect of the antibiotic, as is wellknown. The MIC values measured in the course of the present inventionagainst the tested bacterial strains compared to the initial value werein the normal range of distribution of the experimental set-up, i.e.surprisingly, no degradation of the MIC due to storage could be observedwithin the observational period. Thus, a solution of fosfomycin and anacid at room temperature (and even with autoclaving or with extremetemperature conditions) will maintain its antimicrobial activity over aperiod of at least three months, which contradicts a strongly anchoredprejudice in the art stating that fosfomycin is unstable.

EXAMPLE 1—PREPARATION

In 500 L of water for injection in accordance with Ph. Eur. (8thedition), 26.4 kg of fosfomycin disodium (corresponding to 20 kg offosfomycin) and 500 g of succinic acid are dissolved under sterileconditions. This solution is filled under sterile conditions in 5000infusions bottles (single volume 100 ml). The infusion bottles are eachcapped with a suitable rubber stopper and packaged at 10 pieces per box.

The pH of this solution is 7.5. The solution contained in the infusionbags is ready to use for intravenous administration and is storable atroom temperature for months. When fosfomycin produced by fermentation isused, a sterile filter is inserted upstream in the final fill into theinfusion bottle under sterile conditions.

EXAMPLE 2—STABILITY STUDIES

The objective of the present investigation was to find out whether theantimicrobial activity of fosfomycin with a pH suitable for intravenousadministration is maintained in a solvent suitable for intravenous use.For this, fosfomycin disodium (14.5 mmol sodium/g) and succinic acidwere used to adjust the pH (0.025 grams of succinic acid per gram offosfomycin).

The pH of this solution was 7.5.

A stock solution of 4 g of fosfomycin disodium and succinic acid (0.025grams of succinic acid per gram of fosfomycin, corresponding to about 3g of fosfomycin) in 10 ml destilled water was prepared and divided into5 cryotubes at 2 ml each, and the solution was exposed at differenttemperatures as follows:

Aliquots of 2 ml of the sample were stored at −80° C., at refrigeratortemperature (2-8° C.), at room temperature (20-25° C.), and at 45-65° C.until the test end. Another 2 ml of the stock solution were stored atrefrigerator temperature (2-8° C.) and autoclaved before the tests at125° C. for 30 minutes. After that, all samples were tested for theirantimicrobioal activity.

To determine the antimicrobial activity of fosfomycin, the minimalinhibitory concentration (MIC) of the 4 mentioned bacteria strains wasdetermined by a tube dilution method in microtiter plates usingMueller-Hinton broth. For the inoculation of the microtiter plates, theinoculum was adjusted to 1.5×104 germs/ml. The evaluation was made after24 hours of incubation at 37° C.

Samples were taken, starting with 2,000 μg/ml test substance, diluted bya factor 2. Serial dilutions of 2,000 μg/ml to 1.95 μg/l were prepared.For the detection of the antimicrobial activity and the stability of asolution of fosfomycin and succinic acid in a solvent suitable forintravenous administration, the MIC values were determined afterincubation for 24 hours at 37° C.

The following bacterial strains were used in the studies:

Staphylococcus aureus No. ATCC 49775,

Staphylococcus aureus No. ATCC 33592,

Staphylococcus hominis No. ATCC 1115, and

Escherichia coli No. AG 1215.

The results are shown in Table 1 and are illustrated in FIGS. 1A-1D. Themeasured values of MIC against the tested bacteria compared to theinitial value are within the normal range of distribution of theexperimental set-up, i.e. surprisingly, no degradation of the MIC due tostorage could be observed within the observational period. Thus, asolution of fosfomycin and an acid at room temperature will maintain(and even with autoclaving or with extreme temperature conditions) itsantimicrobial activity over a period of at least three months, whichcontradicts a strongly anchored prejudice in the art stating thatfosfomycin is unstable.

TABLE 1 The table shows the MIC values of the tested bacterial strainsdependent on the storage conditions of fosfomycin (duration andtemperature). Storage-dependent minimal inhibitory concentrations(μg/ml) of Fosfomycin Storage Storage period of Fosfomycin in days temp.(° C.) 0 19 27 31 54 59 64 92 Staphylococcus aureus ATTC 49775 −80 7.83.9 — 3.9 — — — — 4-8 7.8 3.9 — 3.9 — — — — 20-25 3.9 15.6 — 15.6 — — —— 45-65 7.8 7.8 — 7.8 — — — — 125 15.6 7.8 — 7.8 — — — — Staphylococcusaureus ATTC 33592 −80 15.6 7.8 — 7.8 — — — — 4-8 15.6 7.8 — 3.9 — — — —20-25 7.8 15.6 — 7.8 — — — — 45-65 15.6 31.2 — 7.8 — — — — 125 15.6 31.2— 7.8 — — — — Staphylococcus hominis AG 1115 −80 — — 7.8 7.8 7.8 15.615.6 15.6 4-8 — — 15.6 7.8 7.8 15.6 15.6 15.6 20-25 — — 31.2 7.8 15.67.8 31.2 62.5 45-65 — — 15.6 3.9 15.6 15.6 15.6 62.5 125 — — 15.6 7.87.8 15.6 31.2 31.2 Escherichia coli AG 1215 −80 62.5 125.0 62.5 — — 15.662.5 62.5 4-8 62.5 62.5 62.5 — — 62.5 15.6 62.5 20-25 250.0 125.0 31.2 —— 31.2 31.2 125.0 45-65 62.5 250.0 31.2 — — 62.5 62.5 125.0 125 125.0125.0 62.5 — — 31.2 62.5 125.0

EXAMPLE 3—PREPARATION OF THE COMBINATION PREPARATION OF FOSFOMYCIN ANDTERBINAFINE

26.4 kg of fosfomycin disodium (corresponding to 20 kg of fosfomycin),500 g of succinic acid and 0.5 kg of terbinafine HCl are dissolved understerile conditions in 500 L of water for injection in accordance withPh. Eur. (8th Edition). This solution is bottled under sterileconditions in 50,000 bottles (single volume: 10 ml). The bottles areeach sealed with appropriate rubber stoppers and are packaged into a boxat 50 pieces each.

The solution contained in the bottles is ready to use for administrationby inhalation as an aerosol and can be stored at room temperature formonths.

The invention claimed is:
 1. A method comprising storing a closed container, comprising an aqueous solution for parenteral administration, wherein at least a pharmaceutically acceptable salt of fosfomycin and a pharmaceutically acceptable acid are dissolved in the solution at a temperature between 0° C. and 60° C. for at least one month, wherein the pharmaceutically acceptable acid is selected from succinic acid, tartaric acid, lactic acid, malic acid, citric acid, carbonic acid, amino acids, acetic acid, and phosphoric acid.
 2. The method of claim 1, wherein the solution is ready to use for parenteral administration.
 3. The method of claim 1, wherein the solution is ready to use for intravenous administration.
 4. The method of claim 1, wherein the closed container is sealed, wherein the container is closed in a manner such that opening of the container is substantially irreversible.
 5. The method of claim 1, wherein the container is selected from: an ampoule or a breakable ampoule, a puncturable vial, optionally sealed with a protective cap, an infusion bag, and a syringe, optionally a syringe ready for injection.
 6. The method of claim 1, wherein the container is a puncturable vial or an infusion bag, and has an intact septum.
 7. The method of claim 1, wherein the container serves as a light protection for the solution.
 8. The method of claim 1, wherein the solution has a pH value of 6.4 to 8.4.
 9. The method of claim 1, wherein the pharmaceutically acceptable acid is succinic acid and the mass ratio of succinic acid to fosfomycin in the solution is between 30:1 and 50:1.
 10. The method of claim 1, further comprising adding a leaflet; wherein the closed container is enclosed in a package that protects the solution or the closed container from light.
 11. The method of claim 1, wherein at least a pharmaceutically acceptable salt of fosfomycin and a pharmaceutically acceptable acid are dissolved in the solution, wherein the solution includes contains a total dose of fosfomycin equivalent to 1 to 15 grams of fosfomycin.
 12. The method of claim 1, wherein the container is a bag, and the bag is in a package with a leaflet, wherein the package is substantially opaque. 